Steroidal (16,17-c)-(1&#39;,2&#39;,5&#39;)oxadiazoles and methods for their manufacture



United States Patent 3,437,658 STEROIDAL [16,17-c]- 1,2,5]0XADIAZOLES AND METHODS FOR THEIR MANUFACTURE Hans Reimann, Wayne, N.J., assignor to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Nov. 25, 1966, Ser. No. 596,747 Int. Cl. C07c 173/00; A61k 17/00 US. Cl. 260-23955 8 Claims ABSTRACT OF THE DISCLOSURE Novel [16,17-c] [1,2',5]oxadiazole-N-oxide derivatives of steroids of the androstane and estrane series are prepared by reacting a 16,17-oximino steroid of the androstane and estrane series with a reagent selected from the group consisting of nitrous acid generated in situ, an alkaline earth metal hypohalite, and an alkali metal hypohalite. Treatment of the thereby produced isomeric mixture of [l6,l7-c]furoxan derivatives with a tri-lower alkyl phosphite yields novel [16,17-c][l',2',5]oxadiazole derivatives of steroids of the androstane and estrane series. The 1,3,5(10) estratrieno-[16,17-c][1,2,5']oxadiazoles and the N-oxide derivatives thereof are useful as estrogenic agents; the 3-keto-androstanoand 3-hydroxy-androstano [16,17-c][1',2',5']oxadiazoles, the corresponding estrane analogs, the unsaturated analogs thereof as well as the N-oxide derivatives of the foregoing possess anabolic/ androgenic activity.

This invention relates to compositions of matter classified as [16,17-c] [1',2',5]oxadiazole derivatives of steroids of the androstane and estrane series, to methods for their manufacture and to intermediates produced thereby.

The invention sought to be patented in its composition aspect is described as residing in the concept of a molecular structure in which the 16 and 17 positions of the nucleus of steroids of the androstane and estrane series are fused to the 3' and 4 positions of a furazan ring (i.e. of a 1,2,5-oxadiazole nucleus) or to the 3 and 4 positions of a furoxan ring (i.e. of a 1',2,5'-oxadiazole-N-oxide nucleus) thus forming [16,17-c][1',2,5']oxadiazole derivatives and [16,17-c] [1,2',5]oxadiazole-N-oxide derivatives of steroids of the androstane and estrane series, respectively; said derivatives being further characterized by having an oxygen function at C3 selected from the group consisting of ketonic oxygen, hydroxy, lower alkoxy, and hydrocarbon carbonyloxy having up to eight carbon atoms.

The invention sought to be patented in its process aspect is described as residing in the concept of reacting a 16,17-bis-oximino steroid of the androstane and estrane series with a reagent selected from the group consisting of an alkaline earth metal hypohalite, an alkali metal hypohalite (preferably sodium hypochlorite) and nitrous acid generated in situ, for example by using sodium nitrite in acetic acid, whereby is produced in isomeric mixture of [16,17-c1furoxan derivatives, i.e. of [16,17-c] [1,2',5] oxadiazole-2-N-oxide and [16,17-c][1,2',5']oxadiazole- -N-oxide derivatives of steroids of the androstane and estrane series; and treating said isomeric 16,17-c1furoxan derivatives with a tri-lower alkyl phosphite, e.g. triethylphosphite, whereby are produced [16,17-c]furazan derivatives, i.e. [16,17-c][1',2',5']oxadiazole derivatives of steroids of the androstane and estrane series.

The invention sought to be patented in its composition aspect may be described as including compounds having minimally the following structural Formulae I and II:

wherein R is a member selected from the group consisting of hydrogen and methyl; W is a member selected from the group consisting of oxygen and (H,fiOY), Y 'being a member selected from the group consisting of hydrogen and hydrocarbon carbonyl having up to eight carbon atoms; and R is a member selected from the group consisting of hydrogen, lower alkyl, and hydrocarbon carbonyl having up to eight carbon atoms; and when W is oxygen, the 4-dehydro and 4,6-bis-dehydro-analogs of Formula I; and when W is oxygen and R is methyl, the 1,4-bis-dehydroand 1,4,6-tris-dehydro-analogs of Formula I; and when W is (H,BOY), the S-dehydro analogs of Formula I; and the [17,17a-c] [l,2',5]D-homo-analogs of the compounds of Formulae I and II and of the foregoing derivatives thereof; and the N-oxide derivatives of Formulae I and II and of the foregoing derivatives and homologs thereof.

Representative of the hydrocarbon carbonyl groups contemplated at C-3 as depicted by Y, are lower alkanoyl such as acetyl, propionyl, caproyl, capryloyl, propargoyl, acryloyl, cyclopentylacetyl, and the like, as well as aromatic carbonyl groups such as benzoyl and methyl homologs thereof, e.g. 0-, m-, and ptoluyl.

By lower alkyl, as representative of R, are contemplated hydrocarbon radicals having up to 4 carbon atoms such as methyl, ethyl, nand iso-propyl, n-, isoand tertabutyl and the like, of which methyl is preferred.

The foregoing formulae delineations are requisite in order for the composition of matter to fall within the scope of my concept. Other substitutents may be present. For example, a methyl group may be present at the l, 6 or 7 positions, an oxygen function such as keto or hydroxy may be present at the ll-position, and halogen may be present at one or more of positions 4, 6, 9, 11, and double bonds other than those set forth above may be present such as a 9(11)-dehydro bond. The only limiting features of my concept insofar as it pertains to compositions of matter are those set forth above; that is, my novel compounds [l6,17-c] [1',2,5'] oxadiazole and [16,17-c] [1',2',5] oxadiazole-N-oxide derivatives of steroids of the androstane and estrane series having an oxygen function at C3 and having A and B rings which may be saturated or contain unsaturations. My concept thus includes [16,l7-c][l,2,5]-oxadiazole-N-oxides of 3-ketoandrostanes (Formula I, W is oxygen, R is methyl)- 3- keto-estranes (Formula I, W is oxygen, R is hydrogen), 3-hydroxy-androstanes (Formula I, W is H,;8OH, R is methyl), 3-hydroxy-estranes (Formula I, W is H,pOH, R is hydrogen) and 3-esters thereof, 3-hydroxy-l,3,5(10)- estratrienes and the 3-ether and 3-ester derivatives thereof (Formula II), 3-keto-4-androstenes, 3-keto-l,4-androstadienes, 3-keto-4-estrenes, 3-hydroxy-5-androstenes, 3- hydroxy-S-estrenes and esters thereof as well as the D- homo[l7, 17a-c][1,2',5'] oxadiazole and the D-homo- [17,l7a'c][l',2',S] oxadiazole-N-oxide analogs thereof.

As disclosed hereinabove, the [l6,1'7-c][1,2,5]-oxadiazole-N-oxide derivatives of this invention, i.e. the 16,17-furoxans, are produced as an isomeric mixture of the 2-N-oxide and the 5-N-oxide derivatives of the compounds defined minimally by structural Formulae I and II. The structural formulae of the [16,17-c][l',2',5]- oxadiazole-N-oxide nucleus of each of these isomers are as follows:

wherein A represents the steroidal A, B, and C-rings as defined by Formulae I and II.

The oxadiazole (furazan) derivatives defined by Formulae I and II and the oxadiazole-N-oxide (furoxan) derivatives defined by Formulae III and IV are named in accordance with standard rules of nomenclature, the numbering thereof being indicated in above Formulae IV wherein the bond between the l and 2' positions is identified as the a bond and that between the 2 and 3' positions as the b bond, etc. Thus, in the compound names, the [16,l7-c] indicates that the bond between the 16 and 17 positions of the steroidal D-ring is also the c" (or 3',4) bond in the oxadiazole ring; and the [l',2',5'] indicates the respective positions of the oxygen and the two nitrogens in the ring. Similarly, in the D-homoanalogs, [17,l7a-c] indicates that the bond between the l7 and 17a carbon atoms is also the bond in the oxadiazole nucleus.

In this specification and in the claims, when the name of a furoxan (i.e. oxadiazole-N-oxide) derivative of a h compound of Formulae I and II does not specify the position of the oxide function, both the 2-N-oxide and '-N-oxide are implicitly included thereby. Thus, the compound name 3,8-hydroxy 5 androsteno[l6,l7-c]- [1',2',5']oxadiazole-N-oxide inherently includes both the 2-N-oxide isomer of Formulae III, and the 5-N- oxide isomer of Formula IV.

Representative of the preferred compounds of the composition aspect of my invention are the N-oxide (furoxans) derivatives of the compounds defined by Formulae I and II since, in addition to being therapeutically active per se, they also serve as intermediates in the preparation of the furazans (i.e. l',2',5-oxadiazoles) of Formula I which are also therapeutically active. Of the preferred [l,2'5']oXadiaz0le-I I oxido androstanes and estranes, those of particular interest are 3-ket0-4-androsteno[ 16,17-c] l',2,5']oxadiazole-N-oxide, 3 p-hydroxy-S- androsteno[l6,17-c][1',2',5']oxadiazole-N-oxide and 3- methoxy 1,3,5(l0) estratrieno[l6,l7 c][1',2',5']oxadiazole-N-oxide.

The process aspect of this invention comprises two steps, the first of which produces the [16,l7-c1furoxans of this invention (i.e. an isomeric mixture of compounds of Formulae III and IV), the second of which (utilizing the furoxaus of step one as intermediates) produces the [16,l7-c1furazans of this invention (i.e. compounds of Formulae I and II) The physical embodiments of the process aspects of this invention are thus made via a two-step synthesis wherein a 16,l7-bis-oxamino-androstane or a 16,17-bisoxirnino-estrane is treated with an oxidizing reagent, e.g. an alkaline earth metal hypohalite (e.g. sodium hypochlorite) or an alkali metal hypohalite (cg. sodium hypochlorite, potassium hypochlorite and lithium hypochlorite) or with nitrous acid prepared in situ (preferably by the action of sodium nitrite in acetic acid) whereby are produced the androstanoor estrano[l6,l7-c][l,2,5]- oxadiazole-N-oxides ([16,17-c1furoxans) of this invention, which in turn, are then reduced with triethylphosphite whereby are formed the androstanoor estrano- [16,17-c][1,2',5]oxadiazoles ([16,17-c1furazans) of my invention.

The first step of my process (whereby is effected ring closure of the vicinal bis-oximino groups to a furoxan ring) is effected either by means of a hypohalite salt in the presence of alkali or with nitrous acid at low temperatures in a solvent which does not interfere with the reaction. Temperatures utilized may be in the range of 20 to +15 C., and preferably in the range of -5 C. to +5 C. when the reagent is a hypohalite salt, e.g. sodium hypochlorite. Solvents which may be used are such as water, alcohols (preferably lower alkanols), glycols, and mixtures thereof and the alkali preferably used is an alkali hydroxide such as sodium hydroxide. When the reagent is nitrous acid (prepared in situ by the action of an acid, e.g. a lower alkanoic acid, on sodium nitrite) an excess of the lower alkanoic acid may serve as the solvent in the presence of water if desired.

Of particular importance in the first step of the process aspect of this invention is the concept of effective ring closure of vicinal bis-oximino groups to form a furoxan ring by the action of nitrous acid, which concept heretofore has been unknown.

The second step of my process (whereby the oxadiazole-N-oxide nucleus is reduced to form an oxadiazole nucleus) is preferably effected at elevated temperatures usually in the range of ll80 C. with the reagent, triethylphosphite, conveniently serving as solvent or suspending medium. The reaction is preferably carried out under an atmosphere of an inert gas such as argon and nitrogen.

In a preferred mode of my process, a solution of 16,17- bis-oximino-5-androsten-3B-ol and sodium hydroxide in aqueous ethanol at about 0-5 C. is treated with an aqueous solution of sodium hypochlorite for about one to three hours and the 3B-hydroxy-5-androsteno[16,17-c] [1',2,51oxadiazole-N-oxide thereby formed separates as a solid, is removed by filtration, and purified by crystallization from acetone/hexane. The 35-hydroxy-5-androsteno[l6,17-c][l',2,5]oXadiazole-N oxide thereby produced is a mixture of the 2-N-oxide and the S-N-oxide isomers as evidenced by nuclear magnetic resonance data.

The 3 fi-hydroxy-S-androsteno l6, l7-c] l,2',5 ']oxadiazole-N-oxide is then suspended in 'triethylphosphite and heated under an atmosphere of nitrogen at -180 C. for five hours to produce 3p hydroxy 5 androsteno [16,17-c][l,2',5]oxadiazole, which is conveniently isolated by acidifying the reaction mixture (after cooling) and filtering the resultant precipitate. Purification is effected by crystallization from methanol.

The requisite intermediates for the process aspect of this invention are the 16,17-bis-oximino derivatives of steroids of the androstane and estrane series. Of these, some are known, e.g. 16,l7-bis-oximino-l,3,5(l0)-estratrien-3-ol and the 3-methyl ether thereof. Those which are not readily available may be derived from the corresponding 16-oximino-17-keto steroid by reaction thereof with hydroxyla-mine according to procedures known in the art. Thus, for example, 16-oximino-S-androsten-B/S-ol-17- one, upon reaction with hydroxylamine in pyridine yields 16,17-dioximino-5-androsten-3B-ol.

The intermediary 16,17-bis-oximino-steroids of the androstane and estrane series have preferably a 3-hydroxy or a 3-alkoxy group at C-3, although 3-acyloxy derivatives may also be utilized. Some typical 16,17-bis-oximino starting steroids are as follows:

16,17-bis-0ximino-androstan-SB-ol, 16,17-bis-oximino-androstane-3[3,1lp-diol, 16,17-bis-oximino-l9-nor-5-androsten-3B-ol, 16,17-bis-oximino-1,3,5( -estratrien-3-ol 3-methyl ether, 16,17-bis-oximino-1,3,5 (10) -estratrien-3-ol 3-ethyl ether, l-methyl l6,17-bis-oximino-1,3,5(10)-estratrien-3-ol, 16,17-bis-oximino-l,3,5(10),7-estratetraen-3-ol, 16,l7-bis-oximino-l,3,5(10),6,8-estrapentaen-3-ol, 17,17abis-oximino-D-homo-l,3,5( l0)-estratrien-3-ol, 17, 17a-bis-oximino-D-homo-androstan-3,8-01, 16,17-bis-oximino-5-androstene-3/i-1lfl-diol, 3fl-acetoxy-16,17-bis-oximino-5-androstene, 16,17-bis-oximino-1,3,5 (l0) -estratrien-3-ol, and 16, l7-bis-oximino- 1 9-nor-5a-androstan-3 5-01.

In general, when preparing compounds of my invention, it is preferable to introduce ester groups (such as at C3) after introduction of the furoxan ring at C-16 and C-17 (or at C-17 and C-l7a of the D-homo steroids), since, when the oxidation step of my process is carried out in a basic medium, eg with sodium hypohalite in the presence of sodium hydroxide, any ester groups present in the starting steroid such as at C-3 are hydrolyzed. Such groups may then be reesterified according to procedures well known in the art. Thus, 3B-acetoxy- 16,l7-bis-oximino-S-androstene upon reaction with sodium hypochlorite in the presence of sodium hydroxide yields 3t3-hydroxy-5-androsteno[16,17-c] [1,2,5']oxadiazole-N-oxide. Esterification of the foregoing N-oxide with acetic anhydride in pyridine yields 3,8-acetoxy-5-androsteno[16,17-c] [l,2,5] oxadiazole N oxide which upon treatment with triethylphosphite according to my invention yields 3B-acetoxy 5 androsteno[l6,l7-c] [1',2',5] oxadiazole.

The 3-keto function is conveniently introduced into the molecule after preparation of my furoxan (i.e. N-oxide oxadiazoles) derivatives by utilizing conventional oxida tive techniques. For example, 3B-hydroxy-5-androsteno [16,17-c][l',2,5]oxadiazole-N-oxide (prepared according to the preferred embodiment of my process as de scribed hereinabove) upon reaction with chromic/sulfuric acid reagent in acetone (i.e. Jones reagent) yields the corresponding 3-keto derivative, i.e. 3keto-5-androsteno {16,17-c] [1',2',5']oxadiazole N oxide which, in turn, upon treatment with alcoholic sodium hydroxide may be isomerized to the corresponding A -analog, i.e. 3-keto-4- androsteno[l6,l7-c][l',2,5]oxadiazole-N oxide. Alternatively, the latter 3-keto-A compound may be derived in one step from the aforementioned 3-hydroxy-A -precursor according to known techniques such as that utilizing the microorganism Flavobaczerium dehydrogenans, or via chemical means such as an Oppenauer oxidation utilizing aluminum isopropoxide in acetone.

The 3-keto-1,4-androstadieno and the 3-keto-4,6-andros tadieno-furoxans (i.e. the A and A -N-oxido derivatives of Formula I wherein W is oxygen) are preferably obtained by dehydrogenation of the corresponding 3-keto- 4-androsteno-furoxans via chemical procedures. Thus, 3- keto-4-androsteno[16,17-c] l,2,5']oxadiazole N oxide upon treatment with dichlorodicyanobenzoquinone in dioxane yields 3-ket0-1,4-androstadieno[16,17-c] [1',2',5]

oxadiazole-N-oxide which in turn, upon treatment with triethylphosphite according to the process of my invention yields 3-keto 1,4 androstadieno[16,17-c][1,2',5] oxadiazole (i.e. a n -derivative of Formula I wherein W is oxygen). Similarly, treatment of 3-keto-4-androsteno [16,17-c] [1',2',5]oxadiazole I oxide with dichlorodicyanobenzoquinone in the presence of hydrogen chloride yields the zt -analog, i.e. 3-keto-4,6-androstadieno[16, l7-c][1,2,5]oxadiazole-N-oxide which upon treatment with triethylphosphite yields 3-keto-4,6-andr0stadieno[16, 17-c] [1,2,5']oxadiazole (a A -compound of Formula I wherein W is oxygen). Similarly, treatment of the foregoing 3-keto-4,6-androstadieno-furoxan with dichlorodicyanobenzoquinone yields the A -analog thereof, i.e. 3-keto-1,4,6 androstatrieno[16,17-c] [1,2,5']oxadiazole- N-oxide( an N oxide A compound of Formula I wherein W is oxygen) which upon treatment with triethylphosphite yields 3-keto 1,4,6 androstatrieno[ 16,17-c] [1',2,5']oxadiazole.

In general, when derivatives of Formula I having substituents at C 6, C-9 and C-ll are desired, it is preferable that they be present in the molecule prior to introduction of the oxadiazole nucleus at C-l6 and C17, although they may be introduced conveniently into the steroidal furoxans of my invention prior to reduction thereof with triethylphosphite to the furazans of my invention. It is also possible, though not as desirable, to introduce substituents at C6, 9, and 11 for example, into the furazans of Formulae I and II.

For example, a convenient method of preparing a 9u,11fi-halohydrin derivative of Formula I, e.g. 9ot-fluoro 11B hydroxy 3 keto-4-androstenofl6,17-c][1,2,5]- oxadiazole, utilizes as a starting intermediate, 16,17-bisoximino 5 androstene-3/3,11B-diol which, upon reaction with sodium hypochlorite according to my invention yields 35,115 dihydroxy-5-androsteno-[16,17-c] [1',2',5']oxadiazole-N-oxide (an 1lB-hydroxy-N-oxido-M-derivative of Formula I wherein W is (H,,BOH)) which in turn, upon reaction with aluminum isopropoxide in acetone according to known techniques will yield the corresponding 3- keto A analog thereof, i.e. 3-keto-11fl-hydroxy-4-androsteno[16,17-c] [1,2,5]oxadiazole N oxide. Treatment of the foregoing compound with methanesulfonylchloride in dimethylformamide effects dehydration at C-9 and C-11 to yield 3-keto-4,9(11)-androstadieno[16,17-c]- [l',2',5]oxadiazole-b-oxide which, when reacted with N- bromoacetamide and perchloric acid in aqueous dioxane yields the 9a-b10II10-11B-hYdIOXY derivative, i.e. 3-k6tO-9ocbrorno 11B hydroxy 4-androsteno[l6,17-c] [l',25']- o-xadiazole-N-oxide. Reaction of the foregoing 9a,1l,8- bromohydrin with potassium acetate in acetone in known manner effects dehydrobromination to give the 95,115- oxido derivative. Addition of anhydrous hydrogen fluoride or hydrogen chloride thereto yields the corresponding ll/i-halogenohydrin, i.e. 3-keto-9a-chloro-l1,8-hydroxy-4- androsteno[l6,17-c][1',2,5']oxadiazole-N-oxide and 3- keto 9oz fiuoro 11fi-hydroxy-4-androsteno[l6,17-c]- [l,2',5]oxadiazole-N-oxide. Reduction of each of the foregoing with triethylphosphite according to my invention, yields the corresponding furoxans, i.e. 3-keto-9achloro 11B hydroxy 4-anclrosteno[l6,17-c][1',2,5']- oxadiazole and 3 keto 9a-fluoro-1lfl-hydroxy-4-androsteno[16,17-c][l',2',5']oxadiazole, respectively (both of which are 9a-halogeno-l1/3-hydroxy derivatives of A -compounds of Formula I wherein W is oxygen).

The tangible embodiments of the composition aspect of my invention possess therapeutic activity as evidenced by pharmacological tests in animals. For example, a preferred species of my invention, i.e. 3-rnethoxy-l,3,5(10)- estratrieno[16,17-c] [l,2',5] oxadiazole-N-oxide exhibits marked estrogenic activity in the General Hormone Screen when administered subcutaneously in the rat and when tested for anti-atherosclerosis activity via the oral route in rats. In general, the 1,3,5(10) estratrieno[16,l7-c] 7 [1',2',5]oxadiazoles defined by Formula II and the N- oxide derivatives thereof exhibit estrogenic activity and are useful for the treatment of disorders requiring an estrogenic agent and may be administered in similar manner as are known estrogenic agents, the dosage utilized being dependent on the nature and severity of the illness.

The 3 keto-androstano and 3 hydroxyandrostano- [17,16-c] [1',3,5]oxadiazole derivatives of Formula I (i.e. R is methyl), and the corresponding estrane analogs (i.e. R is hydrogen), and the unsaturated analogs thereof, as well as the N-oxide derivatives of the foregoing possess anabolic/androgenic activity. For example, 3-keto-4-androsteno[l6,17-c] [1',2',5]oxadiazole-N-oxide and 3 hydroxy-5-androsteno[16,17-c] [1,2,5] oxadiazole-N-oxide (N-oxide derivatives of Formula I and members of the preferred species of my invention) exhibit anabolic/androgenic activity when tested in the rat via the subcutaneous route in the General Hormone Screen. The compounds of Formula I are, therefore, useful in the treatment of ailments caused by poor utilization of nitrogen and may be administered in a manner similar to that used for known anabolic/androgenic agents, the dose required depending on the nature and severity of the illness being treated.

The physiologically active compounds of this invention, e.g. 3 methoxy-l,3,5(l)-estratrieno[l6,l7-cl[1,2,5]- oxadiazole-N-oxide, 3 'keto 4 androsteno[16,l7-c]- [l',2,5]oxadiazole-N-oxide and 35 hydroxy S-androsteno[16,l7-c][1',2,5]oxadiazole-N-oxide thus may be administered orally or parenterally by incorporating a therapeutic dosage in conventional pharmaceutical form such as tablets, capsules, elixirs, suspension, solution, or the like. They can be administered in admixture with pharmaceutical excipients which are edible and which are chemically inert to the aforementioned [16,17-c] [l,2,5']- oxadiazole-N-oxides, exemplified by cornstarch, lactose, sucrose, gum arabic usually in admixture with an additive such as magnesium stearate, talc, and the like. Other compositions may be used such as fine powders or granules of 3 methoxy-1,3,5(l0)-estratrieno[16,l7-c1- [1',2,5']oxadiazole-N-oxide 3 keto 4 androsteno- [16,17-c][1,2,5]oxadiazole-N-oxide and 3B hydroxy- [16,17-c] [1,2,5] oxadiazole-N-oxide or derivatives thereof, which compositions may contain diluents and dispersing and surface acitve agents and may be presented in a syrup or non-aqueous suspensions, in aqueous suspension, or in an oil.

For purposes of illustration, the preferred mode of carrying out the process of this invention is disclosed in detail below. It will be readily apparent to one skilled in the art that there are alternative ways in which derivatives of the base compounds of my invention (as defined by Formulae I and II) may be obtained. It is to be understood that the examples are merely illustrative of the process and are not to be construed as limiting the invention. Obvious equivalents apparent to one skilled in the art are included in the invention as defined by the appended claims.

EXAMPLE 1 16-oximino-5-androsten-3,B-ol-17-one To a solution of 2.1 g. of potassium in 150 ml. of anhydrous t-butanol add 5 g. if 5-androsten-3B-ol-17-one. Stir the mixture under nitrogen for 30 minutes, then add dropwise 4 ml. of n-butyl nitrite and continue stirring the reaction mixture at room temperature for one hour. Add 150 ml. of cold water and acidity the resulting solution by first adding acetic acid and then hydrochloric acid. Filter the resultant precipitate, wash the residue with water and dry to give 16-oximino-5-androsten-3B-ol-l7- one. Purify by crystallization from acetone-hexane M.P. 239-241 C.

In a manner similar to that described above, treat each of the following 16-unsubstituted 17-keto steroids with n-butyl nitrite and potassium t-butoxide:

Androstan-3B-ol-l7-one,

Androstanc-3;8,11,8-diol-l7-one,

l9-nor-5-androsten-3fi-ol-17-one,

1,3 ,5 (10)-estratrien-3-ol-17-one B-methyl ether (estrone 3-methyl ether),

l-methyl-estrone,

7-dehydro-estrone (equilin),

1,3,5 10)-6,8-estrapentaen-3-ol-17-one (equilenin) D-homoandrostan-hB-ol-17a-one,

5-androstene-3fi,11 8-diol-17-one,

19-nor-5 a-androstan-3fl-ol-17-one,

D-homo-1,3,5(10)-estratrien-3-ol-17a-one,

D-homo-5-androsten-3-ol-17a-one.

Isolate and purify the respective resultant products in a manner similar to that described above to obtain the following products 1A through 1L, respectively:

(1A) 16-oximino-androstan-3fi-ol-17-one,

(1B) 16-oximino-androstane-3 {3,11fi-diol-17-one,

( 1C) 16-oxirnino-19-nor-5 -androsten-3 5-01-17-one,

(1D) 16-oximinoestrone 3-methyl ether,

(1E) 16-oximino-1-methylestrone,

(1F) 16-oximinoequilin,

( 1G) l6-oximinoequilenin,

( 1H) 17-oximino-D-homoandrostan-3fl-ol-17a-one,

(11) 16-oximino-5-androstene-3B,11fl-diol-17-one,

(1] l6-oximino-19-nor-5 a-androstan-S B-ol-17-one,

(1K) 17-oximino-D-homo,1,3 ,5 10) -estratrien-3 -ol- 17a-0ne,

( 1L) 17-oximino-D-homo-5-androsten-3fl-ol-17a-one.

EXAMPLE 2 16,17 -bis-oximino-5-androsten-3 (3-01 To a solution of 3.5 g. of 16-oximino-5-androsten-3fiol-17-one in ml. of pyridine add 3.5 g. of hydroxylamine hydrochloride and keep the reaction mixture at room temperature overnight. Then pour into ice water. Filter the resultant precipitate and wash the residue with water and dry to give 16,17-bis-oximin0-5-androstcn-3B- o1. Purify by crystallization from methanol MI. 262- 263 C. dec.

In a similar manner treat each of compounds 1A through 1L (prepared as described in Example 1) with hydroxylamine hydrochloride. Isolate and purify the resultant respective products to obtain EXAMPLE 3 3 3hydroxy-5-androsteno[16,17-c] [1',2,5 1oxadiazolc-N- oxides 3 [3-hydroxy-5-androsten0 1 6, 17-c1furoxan) (A) Prepare a solution of sodium hypochlorite by bubbling chlorine gas into a 1.0 N sodium hydroxide solution which is chilled in an ice bath. Continue adding the chlorine gas until the solution is no longer alkaline.

Add 2 g. of 16,17-bis-0ximino-5-androsten-3B-ol to a mixture of 88 ml. of 10% sodium hydroxide, ml. of

The 3 8-hydroxy-5-androstene [16,17-c] furoxan thus obtained is a mixture of the two possible N-oxides (i.e. the 2'- and N-oxides) as determined by nuclear magnetic resonance (NMR) spectral data.

(B) Cool in a cold water bath a solution of 75 mg. of 16,17-bis-oximino-5-androsten-3fl-ol in 8 ml. of acetic acid, then add a solution of l g. of sodium nitrite in 1 ml. of water. Keep the reaction mixture at room temperature for minutes, then pour into ice water. Filter the resultant precipitate, then dissolve the filter residue in 2 ml. of acetone and add 2 drops of 6 N hydrochloric acid. Allow this mixture to stand for 45 minutes (to hydrolyze any 3-nitrite ester which may be present). Pour the solution into ice water, filter the resultant precipitate and wash the filtered residue with water and dry to give 3,8- hydroxy-S-androsteno[16,l7-c]furoxan.

In a similar manner, utilizing either of above procedures A and B, each of the l6,17 bis-oximino derivatives 2A through 2L (prepared as described in Example 2) is converted to the following respective furoXan derivative.

(3A) 3 B-hydroxyandrostano[16,17-c]furoxan, 3B) 35,1lfi-dihydroxyandrostano[ l6,17-c]furoxan, (3C) 3,8-hydroxy-19-nor-5-androsteno[16,17-c]furoxan, (3D) 3-methoxy-l,3,5(10)-estratrieno[16,17-c1furoxan, (3E) 1-methyl-3-hydroxy-l,3,5 10) -estratrieno 16,17-c] furoxan, (3F) 3-hydroXy-1,3,5(l0),7-estratetraeno[16,17-c] furoxan, (3 G) 3-hydroxy-1,3,'5( 10) ,6,8-estrapentaeno[ 16,17-c] furoxan, (3H) 3 B-hydroxy-D-homoandrostano 17,17a-c]furoxan, 31) 3,8,11B-dihydroxy-5-androsteno[16,17-c]furoxan, (3] 3fi-hYClI'OXY-19-I1OI-5zx-finClIOS'E21I10[l6,l7-C]fll10X2Il, (3K) 3-hydroxy-D-homo-1,3 ,5 10) -estratrieno- [17,17a-c) ]furoxan, (3L) 3B-hydroxy-D-homo-5-androsteno[17,17a-c) furoxan.

EXAMPLE 4 3-keto-5-androsteno[16,17-c]furoxan To a solution of 100 mg. of 3fl-hydroxy-5-androsteno [16,l7-c]furoxan in 10 ml. of acetone, cooled in an ice bath, add dropWise while stirring the reaction mixture a solution of chromium trioxide in aqueous surfuric acid (Jones reagent) until a permanent orange color is obtained. Add a few drops of methanol, then pour the resulting green solution into ice Water. Filter the resultant precipitate and wash the filtered residue with Water, then dry to give 3-keto-5-androsteno['16,l7-c]furoxan Purify by crystallization from acetone-hexane.

In similar manner treat each of the 3B-hydroxy-furoxan derivatives prepared in Example 3, i.e. compounds 3A, 3B, 3C, 3H, 31, 3] and 3L with chromium trioxide in sulfuric acid in the manner described above. Isolate and purify the resultant products in a manner similar to that described to give, respectively (4A) 3-ketoandrostano[16,17-c1furoxan, 4B) 3,1l-diketoandrostano[16,17-c1furoxan,

l 0 (4C) B-keto-19-nor-5-androsteno[1-6,1-7-c]furoxan, (4H) 3-keto-D-homoandrostano[17,17a-c]furoxan, 41) 3,l1-diketo-5-androsteno[16,17-c]furoxan, (4] 3-keto-19-nor-5u-androstano[ 16,17-c1fur0xan, 4L) 3-keto-D-homo-5-androsteno[ l7,17a-c]furoxan.

EXAMPLE 5 3-keto-4-androsteno 16, 17-c] furoxan Dissolve mg. of 3-keto-5-androsteno[l6,l7-c]furoxan in about 10 ml. of hot methanol, then add sufficient 10% sodium hydroxide solution to adjust the solution pH between 8 and 9. Heat the solution on a steam bath for 5 minutes, then bring to neutrality by the addition of acetic acid, then concentrate to a small volume. Pour the reaction mixture into ice water and filter the resultant precipitate. Wash the filtered residue with water and dry to give 3-keto 4-androsteno[l6,l7-c]furoxan. Purify by crystallization from acetone-hexane M.P. 211- 2.13 C. [a] |3l (dioxan),

In a similar manner treat each of 3-keto-l9-nor-5-androsteno[16,l7-c]furoxan (product 4C) and 3,1l-diketo- S-androsteno[16,l7-c1furoxan (product 41) and 3-keto- D-homo 5 androsteno[ l7,17a-c]furoxan (product 4C) with sodium hydroxide in methanol and isolate and purify the resultant product to obtain, respectively 3 -keto-19-nor-4-androsteno l 6, 17-c] furoXan (product 5 C and 3,1 1-diketo-4-androsteno[16,17-c1furoxan (product SI), and 3-keto-D-homo-4-androsteno[17,l7a-c]furoxan (product EXAMPLE 6 3-keto-4,6-androstadieno[16,17-c1furoxan Cool a solution of 1.0 g. of 3-keto-4-androsteno [16,17-c]furoxan and 750mg. of dichlorodicyanobenzoquinone in 5 0 ml. of dioxane in a water bath and pass a stream of anhydrous hydrogen chloride gas through the solution for one minute. Stir this reaction mixture at room temperature for one hour, then filter off the precipitated hydroquinone. Add ethyl acetate to the filtrate and extract the ethyl acetate solution with 2% aqueous sodium hydroxide, then wash with saturated sodium chloride solution and concentrate in vacuo to a residue comprising 3-keto-4, 6-androstadieno[16,17-c1furoxan.

In similar manner treat 3,1l-diketo-4-androsteno [16,l7-c1furoxan with dichlorodicyanobenzoquinone and hydrogen chloride. Isolate and purify the resultant product in the manner described to give 3,l1-diketo-4,6-androstadieno[16,17-c]furoxan.

EXAMPLE 7 3-keto-1,4-androstadieno[ l6,17-c]fur0xan To a solution of 750 mg. of dichlorodicyanobenzoquinone in ml. of dioxane add 1 g. of 3-keto-4-androsteno[l6,17-c]furoxan (compound 5C). Heat the reaction solution at reflux temperature for 16 hours, then concentrate to a residue of about 30 ml., filter, and add ethyl acetate to the filtrate. Extract the ethyl acetate solution with 2% aqueous sodium hydroxide, then Wash with water, dry over sodium sulfate and concentrate in vacuo to a residue comprising 3-keto-1,4-androstadieno[16,17-0] furoxan. Purify by crystallization from acetone-hexane.

In a similar manner treat each of 3,1'l-diketo-4-androsteno[16,l7-c]furoxan (compound 51) and 3-keto- 4,6-androstadieno[l'6,l7-c]furoxan (compound of Example 6) With dichlorodicyanobenzoquinone at reflux temperature and isolate and purify the resultant product in a manner similar to that described above to obtain 3,11-diketo 1,4 androstadieno[16,l7-c]furoxan and 3- keto-l,4,6-androstatrieno[16,17-c1furoxan, respectively.

1 1 EXAMPLE s 3-keto-9a-halogeno-1 1,8-hydroxy-4- androsteno[16,17-c1furoxan (A) 3-keto-1 lit-hydroxy 4 androsteno[l6,17-c]furoxan.-To a solution of g. of aluminum isopropoxide in 200 ml. of dry benzene add dropwise with stirring a solution of 2 g. of 3/3,115-dihydroxy-5-androsteno- [16,17-c1furoxan in 60 ml. of of acetone. Heat the reaction mixture at reflux temperature for 16 hours, cool and dilute with ether. Wash the ether solution with a concentrated aqueous solution of potassium sodium tartrate, then wash with dilute aqueous sodium carbonate and iinally with water. Dry the ether solution over sodium sulfate and then concentrate in vacuo to a residue comprising 3-keto-11fi-hydroxy 4 androsteno[16,17-c1furoxan. Purify by crystallization from acetone-hexane.

(B) 3-keto-4,9(l1)-androstadieno[16,17-c1furoxan. Heat a solution of 1.0 g. of 3-keto-llB-hydroxy-4-androsteno[16,17-c1furoxan in a mixture of 5 ml. of pyridine and 5 ml. of dimethylformamide to 80 C., then add 0.9 ml. of methanesulfonyl chloride. Maintain the reaction mixture at 80 C. for one hour, then pour into ice water with stirring. Filter the resultant precipitate comprising the 3-keto-4,9(11)-androstadieno[16,17-c1furoxan, wash with water and dry. Purify by dissolving the precipitate in acetone and treating the acetone solution with decolorizing charcoal followed by crystallization from acetone-hexane.

(C) 3 keto 90c bromo-l1fi-hydroxy-4-androsteno [16,17 c]furoxan.-To a solution of 500 mg. of 3- keto 4,9(11) androstadieno [16,17 c]furoxan in 60 ml. of dioxane and 6 ml. of water add 210 mg. of N-bromo acetamide and 3 ml. of 1.5 normal perchloric acid. Allow the mixture to stand at room temperature for 2 hours then add methylene chloride and wash the reaction mixture with a 5% sodium sulfite aqueous solution. Dry the methylene chloride solution over sodium sulfate, filter and evaporate the filtrate in vacuo to a residue comprising 3 keto 9a bromo 11B hydroxy 4-androsteno[16,17-c]furoxan. Purity by crystallization from acetone-hexane.

(D) 3 keto- 95,11 3 oxido 4 androsteno[16, 17 c]furoxan.-Add 2 g. of potassium acetate to a solution of 1 g. of 3 keto 90c bromo 1113 hydroxy- 4 androsteno[16,17-c1furoxan in 200 ml. of acetone. Heat the reaction mixture at reflux temperature for 6 hours then distill the acetone until the reaction mixture is reduced to a volume of about 20 ml. Pour the reaction mixture into ice water and filter the resultant precipitate comprising 3 keto 9,8,115 oxido 4 androsteno- [16,17-c1furoxan. Purify by crystallization from acetonehexane.

(E) 3 keto 90c fluoro 11,6 hydroxy 4-androsteno[16,17-c]furoxan.-Add 1 g. of 3 keto 95,1113- oxido 4 androsteno[16,17-c1-furoxan to a solution of 3.5 g. of hydrogen fluoride in 20 ml. of chloroform and 0.6 ml. of tetrahydrofurane maintained at C. Allow the reaction mixture to stand at -10 C. for 3 hours then pour into aqueous sodium carbonate solution with stirring. Add chloroform, separate the organic and aqueous layers and evaporate the organic layer to a residue comprising 3 keto 90c fluoro 11,8 hydroxy 4 androsteno[16,17-c1furoxan (i.e. 3 keto 9oc-fl110l0- 11B hydroxy 4 androsteno[16,17-c][1',2,5'] oxadiazole N oxide). Purify by crystallization from acetone.

(F) 3 keto 9a. chloro 115 hydroxy 4 androsteno[16,17-c]furoxan.-Bubble hydrogen chloride gas through a solution of 1 g. of 3 keto 95,115 oxido- 4 androsteno[16,17-c1furoxan in 30 ml. of chloroform at 0 C. until the solution is saturated with hydrogen chloride. Keep the mixture at 0 C. for 6 hours then pass a stream of nitrogen through the solution to remove excess hydrogen chloride and then distill the reaction mixture to a small volume. Crystallize the resultant residue from acetone to yield 3-keto-9ot-chloro-1lfi-hydroxy- 4-androsteno[16,17-c1furoxan.

EXAMPLE 9 3B-acetoxy-androstano[16,17-c1furoxan (A) To a solution of 1 g. of 35-hydroxy-androstano [16,17-c1-furoxan in 10 ml. of pyridine add 1 m1. of acetic anhydride. Allow the reaction mixture to stand at room temperature for 16 hours then pour into ice water. Filter the resultant precipitate, Wash with water and dry to give 3,8 acetoxy androstano[16,17-c] furoxan (i.e. 3B acetoxy androstano[16,17-c]{1,2,5]oxadiazole- N-oxide.

(B) In the above procedure by substituting for acetic anhydride other acid anhydrides or halides such as propionic anhydride, caproyl chloride and benzoyl chloride, there is obtained the corresponding ester at C3, i.e. 3,8 propionyloxy androstano[16,17-c1furoxan, 3,8- caproyloxy androstano[l6,17-c] furoxan and 3(3- benzoyloxy androstano[16,17-c]furoxan, respectively.

(C) In a similar manner react each of the following furoxans With acetic anhydride in pyridine according to the procedure of Example 9-A.

3 3-hydroxy-19-nor-5-androsteno[16,17-c1furoxan,

3-hydroxy- 1,3 ,5 10) -estratrieno [16,17-c] furoxan,

1-methyl-3-hydroxy-1,3,5 (10)-estratrieno[16,17-c] furoxan,

3 -hydroxy-1,3,5(10),1-estratetraeno[16,17-c]furoxan,

3-hydroxy-1,3 ,5 10) ,6,8-estrapentaeno 16,17-c] furoxan,

3B-hydroxy-D-homo-androstano[17,17a-c1furoxan,

3fl-hydroxy-19-nor-androstano[16,17-c1furoxan,

3 -hydroxy-D-homo-1,3,5 10) -estratrieno 17,17a-c] furoxan, and

313-hydroxy-5-androsteno[16,17-c1furoxan.

Isolate and purify the respective resultant products in a manner described in Example 9-A t obtain respectively,

3B-acet0xy-19-nor-5-androsteno[16,17-c]furoxan, 3-acetoxy-1,3,5( 10)-estratrieno[16,17-c1furoxan, l-methyl-3-acetoxy-1,3,5(10)-estratrieno[16,17-c] furoxan, 3-acetoxy-1,3,5( 10),7-estratetraeno[ 16,17-c] furoxan, 3-acetoxy-1,3,5(10),6,8-estrapentaeno[16,17-c] furoxan, 3i3-acetoxy-D-homo-androstano[17,17a-c1furoxan, 313-acetoxy-19-nor-androstano[16,17c]furoxan, 3-acetoxy-D-homo- 1,3 ,5 10)-estratrieno[17,17a-c] furoxan, and 3B-acetoxy-5-androsteno[16,17-c1fur0xan.

EXAMPLE 1O 3-keto-4-androsteno[16,17-c] [1',2',5 '1 oxadiazole (3-keto-4-androsteno[16,17-c1furazan Heat a suspension of 500 mg. of 3 keto 4 androsteno[16,17-c] furoxan in 3 ml. of triethyl phosphite at 180 C. under an atmosphere of nitrogen for 5 hours. Cool the reaction mixture then add 3 ml. of Water and 6 ml. of 10% aqueous sulfuric acid. Separate the resultant precipitate by filtration, wash with water and dry to give 3 keto 4 androsteno[16,17-c1furazan. Purify by crystallization from methanol.

Treat each of the following [16,17-c][1,2',5'] oxadiazole N oxide derivatives with triethyl phosphite in a manner similar to that described above and isolate and purify the resultant product in the manner described below:

to give the respective [l6,l7-c]furazan products listed Product 35, 1lfi-dihydroxy-5-androsteno- [16, 17-c]iuroxan. 3t]-hydr0xy-19-nor-5aandr0stano- [16, 17-0]furoxan. 3-h ydroxy-D-homo-1, 3, 5(10)-estratrieno[17, l7a-clfuroxan. 36-hydroxy-D-homo-zl-androsteno- [17, 17a-c]furoxan. 3-ketoandrostano-[16, 17-0]furoxan. 3, 11-diketoandrostano-[16, 17-0] furoxan. 3-keto-19-nor-5-androsteno-[16, 17-0] furoxan. 3-ket0-D-homoandrostano-[17, 17ac]furoxan. 3, 11-diketo-5-andr0steno-[16, 17-0] iuroxan. 3-keto-19-nor-5a-androstano- [16, 17-0]turoxan. 3-keto-D-homo-5-androsten0- [17, 17a-0]furoxan. 3-keto-19-nor-4-andr0steno-[16, 17-0] furoxan. 3, 11-diket0-4-andr0steno-[16, 17-0] furoxan. 3-keto-D-horno-4-androsteno- [17, 17a-0]fur0xan. 3-keto-4, 6-andr0stadieno-[16, 17-0] furoxan. 3-keto-1, 4-androstadieno-[16, 17-0] iuroxan. 3-keto-1, 4, 6-andr0statrien0-[16, 17-

clluroxan. 3-keto-fia-fluoro-llfl-hydroxy-tandrostenoflfi, 170]furoxan. 3-keto-9a-chloro-1lfl-hydroxy4- endrostenoflfi, 17-c]fur0xan. 3-ketoa-brorno-l1,9-hydroxy-4- androstenoflfi, 17-c]fur0xan. 3B-a0et0xy-androstano-[16, 17-0] furoxan. 3-acetoxy-1, 3, 5(10)-estratrien0 [16, 17-c]iuroxan.

3 3, llfi-dihydroxy-S-androsteno- [16,17-c]iurazan. 35-hydr0xy-19-n0r-5a-androstano- [16, 17-c]furazan. B-hydroxy-D-homo-l, 3, 5(10)- estratrienol17, 17a-0]furazan. 35-hydroxy-D-horno-s-androsteno- [17, 17ac]iurazan. 3-ketoandrostano-llfi, 17-c]iurazan. 3, 11-diketoandrostano-[16, 17-0] furazan. 3-keto-19-nor-4-androsteno-[16, 17-c] furazan. 3-keto-D-homoandrostam-[17, 17a- ]furazan. 3, 11-diketo-4-andr0steno-[16, 17-0] turazan. 3-keto-19-nor-5a-andr0stano- [16, l7-clfurazan. 3-ket0-D-homo-4-androsteno- [17, l7a-cll'urazan. 3-keto-19-nor-4-androsteno-[16, 17-0] turazan. 3, 1l-diketo-4-androsteno-llfi, 17-0] turazan. 3-keto-D-homot-androsteno- [17, 17a-c][urazan. 3-ket0-4, 6-androstadien0-[16, 17-0] furazan. 3-keto-1, 4-androstadieno-[16, 17-0] furazan. 3-keto-1, 4, fi-androstatrieno-llfi, 17-

c]furazan. 3-keto-9a-fluor0-115-hydroxy-4- androstenoflfi, 17-c]furazan. 3-1;GlZO-Qa-ClllOIO-llfi-hYdl'OXy-4- androstenoflfi, 17-0]iurazan. 3-keto-9a-bromo-1lfl-hydroxyiandrosteno[1G, 17-0]turazan. 3B-acet0xy-androstano-[16, 17-0] turazan. 3-acetoxy-1, 3, (10) estratrieno [16, 17-0]lurazan.

In the above procedue, when the starting furoxan inn O A l di R and I R O I II wherein R is a member selected from the group consisting of hydrogen and methyl; W is a member selected from the group cansisting of oxygen and (H,BOY), Y being a member selected from the group consisting of hydrogen and hydrocarbon carbonyl having up to eight carbon atoms; and R is a member selected from the group consisting of hydrogen, lower alkyl, and hydrocarbon carbonyl having up to eight carbon atoms; and

when W is oxygen, the 4-dehydro and 4,6-bis-dehydroanalogs of Formula I; and

when W is oxygen and R is methyl, the 1,4-bis-dehydroand the 1,4,6-tris-dehydro-analogs of Formula I; and when W is (H,flOY) the S-dehydro-analogs of Formula I; and the [17,17a-c][l',2',5']D-homo-analogs of Formulae I and II and of the foregoing derivatives thereof; and the N-oxide derivatives of Formulae I and II and of the foregoing derivatives and homologs thereof.

2. A 4-dehydro-N-oxide derivative according to claim 1, Formula I wherein R is methyl and W is oxygen, said compound being 3-keto-4-androsteno [16,17-c][1,2,5] oxadiazole-N-oxide.

3. An N-oxide derivative according to claim 1 Formula II wherein R is methyl, said compound being 3-methoxy- 1,3,5(10) estratrieno[l6,l7-c][1,2',5']oxadiazole N- oxide.

4. A S-dehydro-N-oxide derivative according to claim 1, Formula I wherein R is methyl and W is (H,/3OH), said compound being 3fl-hydroxy-5-androsteno[16,17-0] [1',2',5 oxadiazole-N-oxide.

5. The process for preparing a [l6,17-c][1',2',5'] oxadiazole-N-oxide derivative of a steroid selected from the group consisting of the androstane and estrane series which comprises treating a 16,17-bis-oximino derivative of a steroid selected from the group consisting of the androstane and estrane series with nitrous acid in situ.

. 6. The process according to claim 5 wherein the nitrous acid in situ is prepared by the action of sodium nitrite in acetic acid.

7. The process according to claim 5 wherein said 16,17- bis-oximino derivative is 3,8-hydroxy-l6,17-bis-oximino-5- androstene and wherein said nitrous acid in situ is generated by the action of sodium nitrite in acetic acid, said process comprising treating 3fl-hydroxy-16,17-bis-oximino-S-androstene with sodium nitrite in acetic acid whereby is prepared 3B-hydroxy-5-andr0steno[16,17-c] [1',2',5 oxadiazole-N-oxide.

8. The process according to claim 5 wherein said bisoximino derivative is 3,8-hydroxy-l6,17-bis-oximino- ],3,5(l0)-estratriene and wherein said nitrous acid in situ is generated by the action of sodium nitrite in acetic acid, said process comprising treating 3fl-hydroxy-16,l7- bis-oximino-l,3,5(l0)-estratriene with sodium nitrite in acetic acid whereby is prepared 3,B-hydroxy-1,3,5(l0)- estratrieno[16,17-c] [1,2,5] oxadiazole-N-oxide.

References Cited Freytag et al., Methoden Der Organischen Chemie Stickstotfverbindungen II and III, 1958, Georg Thieme Verlag, Methoden zur Umwandlung von Aminen, pp. 1-221, p. 136 relied on.

Behr, L., Heterocyclic Compounds 1962, Wiley and Sons, New York, London, chapter XI, pp. 283-315, p. 299 relied on.

LEWIS GOTTS, Primary Examiner. E. G. LOVE, Assistant Examiner.

US. Cl. X.R. -51; 260-307, 397.4, 397.5, 397.45, 566, 999

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,437,658

April a, 1965 Hans Reimann It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 4, line 12, hypo- Column 12, line 33, l,3,5(l0) ,7-estratetraeno line 5, insert:

Starting Material 3BHydroxyandrostano [16, l7-c1furoxan 3B,llB-Dihydroxyandrostano [16,17-c] furoxan 3BHydroxy-l9-nor-5-androsteno- [l6,l7c] furoxan 3-Methoxyl,3,5 (.lO)-estra trieno-[l6,l7-c]furoxan l-Methyl-3-hydroxy-l,3,5 (10)- estratrieno [16,17-0] furoxan 3Hydroxyl,3,5 (10) ,7-estratetraeno [l6,l7c] furoxan 3Hydroxyl,3,5 (10) ,6,8estra pentaeno [l6,l7-c]furoxan 3B-Hydroxy-D-homoandrostano- [17,l7a-c1furoxan "e.g. sodium hyposhould read e.g. calcium 1,3,5 (10) ,l-estratetraeno" should read Column 13, at the beginning of the table befox Product 3B-Hydroxyandrostano- [l6,l7c]furazan 3B,llB-Dihydroxyandrostano- [l6,l7-c] furazan 3B-Hydroxy-l9-nor-5-androsteno- [l6,l7c]furazan 3Methoxy-l,3,5 (lO)-estra trieno- [16,17-c] furazan lMethyl-3-hydroxyl,3,5 (10)- estratrieno [16,17-c] furazan 3-Hydroxy-l, 3,5 (10) ,7-estratetraeno [16,17-c1furazan 3Hydroxy-l,3,5 (l0) ,6,8-estrapentaeno [16,17-c] furazan Signed and sealed this 14th day of April 1970.

(SEAL) Attest:

EDWARD M.FLE'ICHER,JR. Attesting Officer WILLIAM E. SCHUYLER, J Commissioner of Patent 

